Anti-cancer drug discovery and development is moving towards a more rational and targeted approach based on our current understanding of the molecular pathogenesis of a variety of human cancers. The application of these new molecularly targeted agents to the treatment of childhood cancers is a focus of this project. The ras family of G-proteins play an important role in the transduction of signals that trigger cell proliferation, and mutations in ras genes are found in 30% of all human cancers. Ras proteins undergo post-translational farnesylation, which is required for activity of wild-type and mutant ras proteins, and this step can be inhibited by farnesyltransferase inhibitors, such as R115777. Patients with neurofibromatosis type 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, including plexiform neurofibromas, with no standard treatment options, other than surgery available. Neurofibromin, which is the product of the NF1 gene, contains a domain with significant homology to ras GTPase-activating proteins. Decreased levels of neurofibromin have been shown to be associated with a constituitively activated ras-GTP status. The evaluation of R115777 in children with refractory solid tumors and neurofibromatosis type I (NF1) is therefore a rational choice. A phase I trial of R115777 for children with refractory solid tumors or NF1 and inoperable plexiform neurofibromas was completed, and based on the results of this phase I trial, a multi-institutional, randomized, double-blinded, placebo-controlled, cross-over phase II trial of R115777 for patients with NF1 and progressive plexiform neurofibromas was developed and is open for patient accrual. The endpoint of this trial is time to disease progression. Automated volumetric MRI analysis is used to evaluate disease progression. In addition, based on a 30% response rate to R115777 in adults with refractory leukemias, we developed a phase I trial of R115777 for children with refractory leukemias, which completed accrual. A series of pharmacodynamic studies evaluating the effect of R115777 are included in the NF1 and leukemia trials. A phase II trial of R115777 is for children and young adults with AML and second complete cytomorphological remission is now in preparation. The endpoints of this trial will be to evaluate the effects of R115777 on disease-free survival and minimal residual disease. Other new agents that are currently in early clinical trials or clinical development include the epothilone B analog and tubulin binding agent BMS-247550, which will soon enter phase II testing in children with refractory solid tumors, the raf kinase and receptor tyrosine kinase inhibitor BAY 43-9006 for refractory cancers and NF1, and the antifibrotic agent, pirfenidone for NF1. A phase I trial of pirfenidone completed accrual, and a phase II trial of pirfenidone for children with NF1 and progressive plexiform neurofibromas is currently open to accrual. The development of clinical trials for NF1 is being expanded to include the development of clinical trials for adults with NF1. A multi-institutional trial of neoadjuvant chemotherapy will be performed to assess the response rate of high grade unresectable sporadic or NF1 associated malignant peripheral nerve sheath tumors (MPNSTs). This trial receives funding through a Clinical Trial Award by the US Department of Defense, and will serve as a platform for the development of novel agents for MPNSTs. Dermal neurofibromas are the hallmark of NF1, and while these tumors do not undergo malignant transformation, they cause significant cosmetic problems and morbidity in NF1. Through collaboration with the NHGRI, a trial to study the natural history of dermal neurofibromas and genetic modifiers in adults with NF1 is in development and receives funding through a Bench to Bedside Award. This trial may lead to treatment studies for individuals with NF1 and dermal neurofibromas.